What is the role of neoadjuvant immunotherapy in non-small cell lung cancer (NSCLC) treatment?

Neoadjuvant Immunotherapy in Non-Small Cell Lung Cancer

Neoadjuvant immunotherapy combined with platinum-doublet chemotherapy is now a standard treatment option for resectable stage IB-IIIA NSCLC (tumors ≥4 cm or node positive), demonstrating superior pathologic response rates and survival outcomes compared to chemotherapy alone. 1, 2

Patient Selection and Indications

Offer neoadjuvant chemo-immunotherapy to patients with:

• Resectable stage IB-IIIA NSCLC (tumors ≥4 cm or node positive) 1, 2
• No known EGFR mutations or ALK rearrangements 1, 2
• Performance status 0-1 3

Critical caveat: For EGFR/ALK-positive patients, neoadjuvant ICI monotherapy should be used judiciously, though combination with chemotherapy may be considered 1

Biomarker Testing - Not Required for Patient Selection

PD-L1 testing is unnecessary for selecting patients for neoadjuvant chemo-immunotherapy. 1, 3 The Chinese expert consensus explicitly states that biomarker detection is not needed for patient selection in the neoadjuvant setting, as benefits are observed across all PD-L1 expression levels 1. This contrasts with metastatic disease, where PD-L1 ≥50% is required for single-agent pembrolizumab 3.

Treatment Regimen and Duration

Administer 2-4 cycles of neoadjuvant immunotherapy: 1

• Platinum-doublet chemotherapy plus PD-1/PD-L1 inhibitor 1
• Standard regimen: carboplatin/pemetrexed plus pembrolizumab for adenocarcinoma 3
• Conduct reviews every 2 cycles to assess treatment efficacy 1

FDA-approved regimen: Nivolumab in combination with platinum-doublet chemotherapy is specifically indicated for neoadjuvant treatment of resectable NSCLC 2

Efficacy Data - Superior to Chemotherapy Alone

The phase III CheckMate-816 study demonstrated that neoadjuvant nivolumab plus platinum-doublet chemotherapy achieved significantly higher rates compared to chemotherapy alone: 1

• Higher pathologic complete response (pCR) rates 1
• Higher major pathologic response (MPR) rates 1
• Higher objective response rates (ORR) 1

A 2023 meta-analysis of 66 studies confirmed these findings, showing neoadjuvant chemo-immunotherapy versus chemotherapy alone achieved: 4

• 7.63-fold higher odds of pCR (OR 7.63; 95% CI 4.49-12.97; p<0.001) 4
• 49% reduction in progression risk (HR 0.51; 95% CI 0.38-0.67; p<0.001) 4
• 49% reduction in mortality risk (HR 0.51; 95% CI 0.36-0.74; p=0.0003) 4
• Similar toxicity rates (OR 1.01; 95% CI 0.67-1.52; p=0.97) 4

Response Assessment

Use PET-CT plus serum tumor markers and/or ctDNA load for assessing efficacy of neoadjuvant immunotherapy 1, 3. The main outcome indicators should include MPR and pCR 1.

Pathologic response predicts survival: Achieving pCR was associated with 75% reduction in progression risk (HR 0.25; p<0.001) and 74% reduction in mortality risk (HR 0.26; p=0.005) 4

Surgical Timing and Safety

Perform surgery 4-6 weeks after completing neoadjuvant immunotherapy. 1, 3 The negative influences of neoadjuvant immunotherapy on surgery remain ambiguous, but preoperative and intraoperative unresectability rates appear comparable to neoadjuvant chemotherapy alone 1, 5.

Grade ≥3 toxicity rate: The pooled estimate is 18.0%, which is similar to chemotherapy alone 4

Adjuvant Maintenance Therapy

For patients achieving MPR or pCR with neoadjuvant immunotherapy, administer 1-year maintenance immunotherapy. 1, 3 The FDA-approved approach includes nivolumab as single-agent adjuvant treatment after surgery following neoadjuvant nivolumab plus chemotherapy 2.

The NADIM trial demonstrated that neoadjuvant nivolumab plus chemotherapy combined with adjuvant nivolumab achieved: 1

• Median DFS of 21.4 months 1
• 3-year OS rate over 80% 1

For stage II-IIIA disease, adjuvant atezolizumab improves disease-free survival (42.3 vs 35.3 months, p=0.02) regardless of PD-L1 status 1, 3

Special Populations

Borderline resectable locally advanced NSCLC: Immunotherapy or induction chemotherapy may provide surgical opportunity for these patients 1

COPD comorbidity and driver mutation-positive patients: These represent critical unresolved challenges requiring individualized assessment 6

Common Pitfalls to Avoid

• Do not delay treatment waiting for PD-L1 results - biomarker testing is unnecessary for neoadjuvant chemo-immunotherapy selection 1, 3
• Do not use ICI monotherapy in EGFR/ALK-positive patients without careful consideration 1
• Do not perform surgery too early - wait the full 4-6 weeks after completing neoadjuvant therapy 1, 3
• Do not omit adjuvant immunotherapy in responders - 1-year maintenance is recommended 1, 3